A 19 days old baby, was delivered by LUCS at 35 weeks of gestation weighing 2100 g, was completely well upto 15 days. He developed jaundice & treated with phototherapy. After two days he got normal saline bolus, antibiotics and blood transfusion for septic shock. 2 hours following blood transfusion his lower extremities became cyanosed with progressive blackening of both feet and legs. Peripheral pulses were absent in both lower limbs. Baby was diagnosed as Preterm (35 weeks) LBW (2100 g), LONS, neonatal jaundice, thromboembolism. Immediate consultation from vascular surgeon taken, Heparin infusion started and antibiotics changed. Since then baby’s condition is gradually improving.

Thromboembolism in newborn Dr. Md Hanif Sumon Resident (Phase-A) Dept. of Neonatology BSMMU

Dr. Md. Shameem Resident (Phase-B) Dept. of Neonatology BSMMU

Normal haemostatic mechanism

There are four phases to the normal coagulation cascade:Blood vessel

constrictionPlatelet aggregationFibrin generationVessel repair and

fibrin degradation

Basic steps of blood coagulation

3 Basic steps of blood coagulation:

Step-1 :Generation of prothrombin activator(Factor-x) by extrensic or intrinsic pathway.

Step-2: Conversion of prothrombin to thrombin by prothrombin activator.

Step-3: Conversion of fibrinogen to fibrin(clot) by thrombin.

Intrinsic clotting system

The intrinsic clotting pathway requires at least four coagulation proteins and two co-factors.

Tested using the aPTT.

Activation of intrinsic pathway

The intrinsic pathway is initiated by the exposure of blood to a negatively charged surface and activation of Factor XII.

Extrinsic clotting system

The extrinsic system, in contrast, requires only one coagulation protein and two co-factors (Ca & TF ).

Extrinsic pathway is assed

with PT.

Activation of extrinsic pathway

Tissue thromboplastin (tissue factor) is present on the surface of perivascular tissue cells but is only exposed to blood flow during injury.

Thromboplastin, in the presence of calcium, binds to Factor VII to cause the activation of Factor X.

The two pathways feed into the common pathway

Physiology

Fibrinolysis To restore vessel

patency, the clot must be organized and removed by plasmin while wound healing and tissue remodeling occur.

Abnormal hemostatic mechanisms

Pathophysiology Thrombus is a solid mass formed in the circulation from the

constitution of the blood during life. It is composed of : Fibrin Platelets Red cells Fate of thrombus: Propagation : complete obstruction

Embolization Dissolution by fibrinolytic activity Organization and recanalization

Embolus Any intravascular solid, liquid or gaseous mass carried by the blood to a site distant from its point of origin. 99% arise from thrombi, so the term thromboembolism.

Virchow Triad in Thrombosis

Hemostatic system of neonate

Hemorrhage > thrombosisThe vascular endothelium system has not accumulated

damage from disease or acquired factor.Levels of vitamin K related clotting factor are low.Antithrombin, protein C, protein S levels are low.Decreased fibrinolytic potential.

Epidemiology Thrombosis occurs more frequently in the neonatal period than

at any other age in childhood. 2.4 per 1,000 admissions to the NICU in Canada 5.1 per 100,000 live births in Germany Male and female equal<10% is idiopathic.

RISK FACTORS Indwelling vascular catheter is the single greatest risk factor for

arterial or venous thrombosis. Indwelling catheters are responsible for >80% of venous and

90% of arterial thrombotic complications. Others:Maternal: autoimmune disorder, PROM, IUGR, diabetes, pre-

eclampsia, oligohydramnios, prothrombotic disorder, chrioamnionitis, family history of thrombosis, antiphospholipid or anticardiolipin antibody.

Delivery: instrumentation, traumatic delivery, emergency cesarean section. FHR abnormalities

Neonate: prematurity, sepsis, birth asphyxia, dehydration, congenital heart disease, polycythemia, SGA, RDS, NEC, pulmonary HTN, congenital nephrotic syndrome, DIC, prothrombotic disorder, shock.

Inherited: protein C & S deficiency, antithrombin deficiency, factor 5 leiden mutation, prothrombin G20210A mutation & others.

Types of Neonatal Thrombotic Disorders

1) Inherited thrombotic Disorders 2) Acquired thrombotic disorders

Inherited thrombotic Disorders

Protein C deficiency Protein S deficiency Anti-thrombin deficiency Factor v Leiden Prothrombin20210A mutation

Acquired thrombotic disorders Catheter-related thrombosis Venous thrombosis Arterial thrombosis

Non-Catheter-related thrombosis Renal vein thrombosis

Neonatal stroke

Inherited thrombotic Disorders

Early age of onset, Spontaneous thrombotic events Extensive venous thrombosis Ischemic skin lesions or purpura fulminans A positive family H/O neonatal purpura fulminans

SPECIFIC CLINICAL CONDITIONS …. Venous thrombosis : Deep vein thrombosisDifficult to determineMay be clinically silentPresent with swelling and discoloration of limb or face

and head, superior vena cava syndromeMay progress to pulmonary embolism or neonatal stroke

Right atrial thrombosis:Thrombosis of superior vena cava with

extension in to the right atrium6% of all neonatal thrombosis>50% asympmtomatic, detected incidentally

during echo50% present with respiratory distress, new

murmur, heart failure, tachyarrythmia

Renal vein thrombosis:Upto 10% of venous thrombosis in newborn80% of non catheter related thrombosis.Common on the left sideClassical triad includes hematuria, palpable

abdominal mass and thrombocytopenia.Other features- HTN, proteinuria, renal impairment.USG- enlarge echogenic kidneys with attenuation or

loss of cortico-medullary differentiation.Color flow doppler- absence of flow in the main or

arcuate renal veinComplication : adrenal hemorrhage, renal failure,

HTN

Venous thrombosis: cerebral sinovenous thrombosis

Thrombosis of cerebral veins or dural sinusSuperior and lateral sinuses most frequently

involvedPresent with seizure, apnea, lethargy

Arterial thrombosis: arterial ischemic stroke (AIS)Mostly occur in middle cerebral artery of left

hemisphere.AIS is a common underlying cause of neonatal

seizures in full term newborn.Present with seizures, apnea, asymmetrical

motor development, hemiplagia.Long term morbidity in 1/3rd affected newborn

are hemiparesis, speech delay, language delay.

Arterial thrombosis: Purpura fulminansRare, rapidly progressive, often fatal Present with DIC and hemorrhagic necrosis of

the skin due to dermal vessel thrombosis.Due to protein C or S deficiency

Approach to thromboembolismHistory:

Family history of such disorderMaternal history of SLE and/or anti-phospholipid

synPositive risk factorTreatment history

Physical Examination:Assessment of severity

Area of involvement Skin color & compare with other extremity- whether

swollen, cyanotic, hyperemic, discolored, distended superficial vein

Pulses of affected extremityPresence of any catheterAssessment of vital organ function.

Laboratory studies1. Coagulation profile: PT, aPTT, TT, plasma fibrinogen

conc.2. Hct3. Platelet count: thrombus itself and heparin can cause

thrombocytopenia4. Genetic test: Protein C and S activity levels

Antithrombin activity assay,Factor V G1691A (Leiden mutation), Prothrombin G 20210A.

Imaging and other studyAccording to organ involvement:Real-time USG with color doppler for diagnosis

and monitoring.Contrast angiography ( the gold standard)Contrast venographyA plain radiograph of the abdomen for catheter

placement.USG or CT of head for sinovenous thrombosis or

IVH.MRA for ischemic neonatal stroke

“Recommendations for neonatal treatment are based on -

extrapolation of principles of therapy from older children & adult guidelines,

limited clinical information from registries, individual case studies and knowledge of current common clinical

practice”

Management of Neonatal Thrombosis

Supportive careAnticoagulation ThrombolysisSurgeryCounseling

Supportive care:Prompt removal of catheter if possibleEmergency consultationLocal care of the woundElevation of footTreamtent of

volume depletion Electrolyte imbalanceSepsisAnemiaThrombocytopenia

Choice of therapy Small asymptomatic non-occlusive arterial or venous

thrombi related to catheters: Catheter removal and supportive care . Large or occlusive arterial /venous thrombi : Anticoagulation with heparin or LMWH Massive venous thrombi or arterial thrombi: Thrombolysis

Surgery [NB- Oral anticoagulant drugs – not recommnaded for neonate]

AnticoagulationUnfractionated heparin:

Heparin binds with antithrombin III (AT), causing conformational change that inactivates thrombin and other proteases most notably factor Xa.

Target aPTT level 60-85 secondsDuration 5-14 days but can be used upto 3 months.Reversal agent protaminComplications : Bleeding, Heparin-induced thrombocytopenia,

osteoporosis

Unfractionated Heparin Dosage MonitoringDose Check APTT

loading 75 U/Kg After 4 hrsMaintenance 28 U/Kg/hr Daily or 4 hrs after dose

changeAdjust APTT level as below:

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

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

decrease by 15% 4 hrs

LMWH (Enoxaparin)Has less effect on thrombin compared to heparin,

but about the same effect on Factor Xa.Duration 5 days to 6 monthsside effects : No major bleeds in premature

neonates Soreness from injection/catheter, leakage, bruising .

LMWH

Dosage Monitoring and Adjustment of LMWH

LMW Heparin(ENOXAPARIN)Dose 1.5 mg/kg/dose twice dailyMonitoring anti-factor Xa Level (Therapeutic level

is 0.5—1.0 U/ml)

Check 4-6 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 LMWHHeparin LMWH

1. Requires IV access2. 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- to degrade fibrindissolve fibrin clot

Indication: Not recommended unless major vessel occlusion causing critical organ or limb compromise.

Outcome: In older children vascular patency 50% with anticoagulant therapy, following thrombolytic therapy > 90%.

If thrombolytic treatment >24 hours monitor plasminogen conc or FFP infusion.

Treatment with heparin after thrombolytic therapy is recommended.

Thrombolytic Therapy

Thrombolytic Agents

tPA : No loading dose 0.1-0.6 mg/kg/h over 6 h

followed by heparin

Streptokinase: Loading-2,000 U/kg over 10 min then 1,000-2,000 U/kg/h .Only one course should be given

for 6 h

Urokinase:

Contraindications to Thrombolytic/Anticoagulation Therapy

AbsoluteCNS surgery or ischemia (including birth

asphyxia) within 10 daysActive bleedingInvasive procedures within 72 hoursSeizures within 48 hours

RelativePlatelet count < 50000/cmm (100000/cmm for

ill neonates)Fibrinogen concentration < 100mg/dLSevere coagulation deficiencyHypertension

Surgical thrombectomyNot done in majority of neonates Microsurgery with thrombolytic regimen is

successfully used in few isolated cases.

PrecautionsIntramuscular (IM) injections and arterial punctures

during anticoagulation or thrombolytic therapy should be avoided.

Indomethacin or other antiplatelet drugs during therapy should be avoided. .

Use minimal physical manipulation of the patient. Thrombolytic therapy should not be initiated in the presence

of active bleeding.

Monitor for thromboembolic complication in all newborn with any catheter.

heparin is often added to neonatal infusions as it prolongs patency

Umbilical lines should be removed as early as possible. UAC <5 days and UVC < 14 days

Prefer a peripheral arterial lines If there is difficulty infusing consider thrombotic eventUse UAC with a hole at the end not at the sideA PICC lines has lower incidence of thrombosis.