THROMBOEMBOLIC DISEASES OF CHILDHOOD

Dr. Tariq Roshan

Need of the well designed prospective trials.

Need of appropriate diagnostic strategies

Confirmatory diagnostic test

Need to establish standard drug regimens of different anti-thrombotic agents for

Prevention treatment

Out line for discussion

Inherited thrombotic disorders

Anti-thrombin deficiency Neonatal Purpura Fulminans (Homozygous Protein C & S deficiency) Activated protein C resistance

Acquired thrombotic problems

Non catheter related events Catheter related events

Congenital thrombophilia

Defined as having a positive family history Early age of onset of TE & Frequent recurrence It is suggested that the children with spontaneous TEs should be investigated History is important and carefully taken history will help in ordering investigations

Clinically the most significant inherited prothrombotic disorders are

AT PC PS APCR/FvL Prothrombin G20210 polymorphism Increased levels of factor VIII, IX, XI

And recently

Plasma lipoprotein (a) levels

The occurrence of thrombosis in children of families with estiblished AT, PC, PS def. & FvL mutation was found to be low?

Acquired risk factors were major contributors to the occurrence of TE

The mean age at first TE was between 30 and 40 years but in females it is 20 years earlier than male in these families There is paucity of information on risk and benefits of long-term prophylaxis versus careful monitoring with intermittent prophylaxis

Anti-thrombin deficiency

Single chain GP, synthesized in the liver

Serine protease inhibitor superfamily Direct inhibitor of thrombin Also inhibits Xa, IXa, XIa & XIIa Most important regulator of fibrin production Quantitative Functional II RS (reactive site defect) II HBS (heparin binding site defect) II PE (multiple site defect)

Type I

Type II

Neonatal period and AT deficiency

There is some protection against the effect of AT deficiency during the neonatal period
Differences in the relative proportions of direct thrombin inhibitors (ATIII, HCII & 2 M) Proportionately more thrombin is inhibited by 2 M than in adult plasma and Small but significant increase in the relative amount of thrombin bound to HC II

Clinical features

Homozygous AT type II deficiency has veen recorde only very rarely Type I defects are probably incompatible with life Type IIHBS is rare but homozygous type tend to present early with severe thrombotic disorder Heterozygous AT def. tend to present in 2nd decade Both venous and arterial events can occur

Aortic thrombosis, multiple thrombotic events including MI and cerebral dural sinus thrombosis during the first few days of life have been reported.

Diagnosis

At birth the levels are 50% and still lower in premature The level further decreases in the event of thrombosis and n sick children The levels of heterozygous overlap with physiologic while homozygous are easy to diagnose Sequential levels and family studies are crucial

Neonatal Purpura Fulminans (Homozygous Protein C & S deficiency)

Reported in homozygous or compound heterozygous Homozygous protein S is even rarer and the history shows consanguineous parents Activated protein C has anti FVa & FVIIIa activity

Most effective when bound to thrombomodulin on endothelial surface

Activated protein C has also profibrinolytic acitvity

Clinical feature

Homozygous cases presents as life threatening disorder in neonatal period Microcirculation is affected first (purpura fulminans), with features of DIC

Due to capillary lesions Initially small mainly at extremities and pressure points or at site of previous trauma

Cerebral and renal vein thrombosis are also seen Ocular manifestations

Retinal hemorrhage Partial or complete blindness

Diagnosis

DIC screening is positive

PT, APTT, TCT prolong Low platelet and fibrinogen MAHA

Definitive diagnosis difficult; levels of PC & PS are low at birth Undetectable Proteins activity and heterozygous levels in parents help in diagnosis

Management

Replacement of deficient factors

Initially FFP Now specific protein C concentrates are available Starting dose 40u/Kg (adjusted after acute phase) Levels >0.25 units/ml considered normal No protein S concentrate available so FFP is the choice

Long term therapy needs to be establish and later therapy is replaced by oral anticoagulant

Activated protein C resistance

In more than 90% APC resistance is due to single point mutation in the gene of FV

The mutation renders the mutant FVa less sensitive to inactivation

Diagnosis is based o the detection of abnormal resistant APC Confirmation by molecular studies which is even more important in neonates

Acquired thrombotic problems

The peak incidence is at the age of less than 1 year Can be classified as
Catheter related Non catheter related

Systemic venous thromboembolism DVT / PE Renal vein thrombosis Systemic arterial thrombosis

Non catheter related events

Spontaneous events are uncommon in neonates Other frequently encountered risk factors in children
Cancer / chemotherapy Cardiac disease Surgery / infection and trauma

Infrequent risk factors

Autoimmune disease Nephrotic syndrome Thalassemia

In adults 40% of DVT / PE idiopathic In children only 5% are idiopathic Renal vein thrombosis though rare can occur during the neonatal period and present during the first few days of life

Flank mass with hematuria Proteinuria and non functioning kidneys Thrombocytopenia In quarter of cases thrombosis is bilateral and may involve inferior vena cava

Pathogenesis poorly understood

Perinatal asphyxia Dehydration Polycythemia Sepsis Nephrotic syndrome, maternal diabetes Congenital heart disease

Non catheter related systemic arterial thromboembolic disease are rare

Takayasus arteritis Arteries of transplant organs Giant coronary aneurysms TEs occurs at the rate up to 23% in mechanical valves

Catheter related thrombosis

Catheter related events are upto 90% in the first year of all thrombotic events Diagnosis is missed in 80% of cases if only ultrasound is used Gold standard test for diagnosis

DVT / Arterial thrombosis is venography and angiography PE with V/Q scan

Management

Remain largely undefined

Supportive care Anticoagulant therapy

Heparin LMWH Warfarin

Thrombolytic therapy Surgery

Unfractionated heparin

The optimal dose is different in children due to biological differences

50units/kg loading dose Followed by continuous infusion of 20 units/kg/h

The levels of antithrombin in children are low as compare to adults Thus there is relative heparin resistance Quicker heparin clearance due to increase volume disturbance

Aptt results do not always predict a therapeutic heparin concentration On the other hand heparin assay result in an underestimate due to the reduced concentration of antithrombin Bleeding is the major problem HIT is rare in children

LMWH

Predictable pharmacology Lack of interaction with other drugs Reduced risk of HIT and oesteoprosis

Oral anticoagulant

OAs should be avoided in the first month of life Use is restricted for prophylaxis of mechanical heart valve Bleeding is the main complication Long term use also results into decrease bone density

Thrombolytic therapy

Massive pulmonary embolism In children thrombolysis is down regulated and thrombolytic therapy is impaired due to reduced concentration of plasminogen.