Overview And Indications For Evaluation
- Incidence of thrombosis lower in children compared to adults; carries significant pediatric morbidity and mortality.
- Peak incidence occurs in infants <1 year and adolescents.
- Healthy infants <6 months exhibit physiologically reduced vitamin K-dependent coagulation factors (II, IX, X) and thrombin inhibitors (Protein C, Protein S, Antithrombin, plasminogen).
- Consider thrombophilia evaluation lacking apparent acquired risk factors (central venous catheters, immobilization, combined oral contraceptives).
- Specific indications for evaluation include:
- Recurrent or life-threatening venous thromboembolism (VTE) starting in infancy or childhood.
- Family history of VTE before age 45.
- History of multiple spontaneous abortions or stillbirths.
- Multiple gene defects frequently coexist; clinical penetrance reflects cumulative genetic burden.
Pathophysiology And Mechanisms
- Thrombosis precipitated by impaired neutralization of thrombin or failure to control thrombin generation.
- Malfunction of natural anticoagulant systems disrupts blood fluidity.
- Venous thrombi contain extensive fibrin, erythrocytes, and leukocytes (red thrombus); develop under slow blood flow conditions.
- Arterial thrombi consist of tightly coherent platelets with minimal fibrin (white thrombus); result from vascular wall damage under rapid blood flow.
Classification Of Hypercoagulable States
| Hereditary (Loss Of Function) | Hereditary (Gain Of Function) | Mixed / Acquired |
|---|---|---|
| Antithrombin deficiency | Factor V Leiden | Previous VTE |
| Protein C deficiency | Prothrombin FII G20210A | Hepatic cirrhosis / Severe liver disease |
| Protein S deficiency | Elevated Factor VIII, IX, or XI | Nephrotic syndrome |
| Hyperhomocysteinemia | Dysfibrinogenemia | Antiphospholipid antibody syndrome |
| Plasminogen deficiency | Elevated Lipoprotein(a) | Medications (L-asparaginase, hormonal therapy) |
Specific Inherited Thrombophilias
Factor V Leiden Mutation
- Single point mutation (G to A) at nucleotide 1691 within factor V gene.
- Arginine replaced by glutamine at position 506 (R506Q).
- Renders activated factor V resistant to inactivation by activated protein C (APC).
- Single most common inherited thrombophilia in Caucasian populations (3-7% prevalence).
- Heterozygous state increases VTE risk 5-10-fold.
Prothrombin G20210A Mutation
- G-to-A transition in 3' untranslated region of prothrombin gene.
- Results in abnormally high prothrombin levels.
- Promotes increased thrombin generation.
- Second most common inherited thrombotic defect (1-4% prevalence).
- Clinical presentation usually milder than homozygous deficiencies of natural anticoagulants.
Natural Anticoagulant Deficiencies
- Antithrombin Deficiency: Impaired neutralization of thrombin, FXa, FIXa, FXIa, FXIIa. Heterozygous state increases VTE risk 10-fold.
- Protein C Deficiency: Vitamin K-dependent plasma glycoprotein. Activated PC inactivates factor Va and factor VIIIa. Homozygous or compound heterozygous neonates present with severe purpura fulminans, progressive skin necrosis, and disseminated intravascular coagulation (DIC).
- Protein S Deficiency: Vitamin K-dependent anticoagulant; functions as cofactor enhancing PC activity against FVa and FVIIIa. Homozygous defects cause neonatal purpura fulminans.
Other Inherited Prothrombotic Risk Factors
- Dysfibrinogenemia: Autosomal dominant condition resulting from impaired thrombin binding to abnormal fibrin. Defective fibrinolysis promotes thrombosis. Characterized by prolonged thrombin time, normal fibrinogen antigen, and reduced fibrinogen activity.
- Hyperhomocysteinemia: Elevated homocysteine levels associated with venous and arterial thromboses. Often linked to cystathionine beta-synthase deficiency.
- Elevated Lipoprotein(a): Competes with plasminogen, regulating fibrinolysis. Independent risk factor for pediatric stroke and VTE.
- Elevated Factor VIII: Polygenic elevation increases thrombosis risk; acts as acute-phase reactant.
Acquired Thrombophilia: Antiphospholipid Syndrome
- Antiphospholipid antibody syndrome (APS) characterized by recurrent fetal loss and/or thrombosis.
- Autoantibodies include lupus anticoagulant, anticardiolipin antibodies, and anti-beta-2 glycoprotein I.
- Triple positive (all three antibodies present) markedly increases thrombosis risk.
- Diagnosis requires positive clinical and laboratory abnormalities identified on two separate occasions at least 12 weeks apart.
- Catastrophic APS features rapid onset of multiorgan thrombosis/microangiopathy; potentially fatal.
Clinical Manifestations
| Location Of Thrombus | Clinical Presentation | Diagnostic Modality |
|---|---|---|
| Venous Thrombus (Limbs) | Swelling, pain, erythema | Venous ultrasonography with Doppler |
| Arterial Thrombus (Limbs) | Cool limbs, diminished/absent pulse | Arterial ultrasonography with Doppler |
| Cerebral Venous Sinus | Headache, vomiting, lethargy, altered mental status | MR or CT venography of head/brain |
| Pulmonary Embolism | Chest pain, dyspnea, pleuritis, tachypnea | CT angiography |
| Portal Vein | Abdominal pain, vomiting, anorexia, splenomegaly | Right upper quadrant ultrasonography with Doppler |
| Renal Vein | Hematuria, abdominal mass, flank pain, thrombocytopenia | Renal ultrasonography with Doppler or CT |
Diagnostic Evaluation Nuances
- Routine screening tests (PT, aPTT) lack utility for hereditary thrombotic disorders.
- Specific functional coagulation testing required for diagnosis.
- Healthy neonates possess physiologically reduced concentrations of PC, PS, and AT.
- Protein C levels remain below adult normal ranges throughout much of childhood.
- Requires age-adjusted pediatric normal ranges for accurate interpretation.
- Nongenetic factors profoundly influence testing: acute thrombosis, infection, inflammation, hepatic dysfunction, nephrotic syndrome, medications, vitamin K deficiency.
- Detailed assessment of inherited thrombophilia best performed 3 months post-event and after discontinuing anticoagulation. Gene testing (e.g., Factor V Leiden) remains unaffected by acute events/anticoagulation.
Management Strategies
Acute Thrombosis Management
- Initiate systemic anticoagulation with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH).
- Switch to vitamin K antagonists (warfarin) or direct oral anticoagulants (DOACs) for subsequent management.
- Catastrophic APS requires aggressive anticoagulation, plasmapheresis, and/or immunosuppression.
Disease-Specific Interventions
- Neonatal Purpura Fulminans (Homozygous PC/PS Deficiency): Requires immediate empiric replacement with fresh-frozen plasma (FFP). Specific purified PC concentrates highly effective. Long-term oral warfarin indicated.
- Antithrombin Deficiency: Heparin administration often ineffective due to deficient AT target. Severe deficiency requires specific AT concentrates or FFP in conjunction with heparin.
- Arterial Thrombosis: Antiplatelet therapy (aspirin 1-5 mg/kg/day) inhibits cyclooxygenase, preventing thromboxane A2 production; indicated for pediatric stroke, Kawasaki disease, and specific cardiac defects.
Duration Of Therapy And Prophylaxis
- Provoked DVT requires 6-12 weeks of anticoagulation.
- Unprovoked DVT requires prolonged anticoagulation (3-6 months minimum).
- Indefinite lifelong anticoagulation indicated for high-risk inherited thrombophilias (PS, PC, AT III deficiency, homozygous FV Leiden, homozygous prothrombin gene mutation) and APS patients after first VTE.
- Primary prophylaxis (LMWH) advised for asymptomatic first-degree relatives with high-risk thrombophilia during precipitating events (surgery, trauma, immobilization, postpartum).
- Recurrence risk: 4.8% with no genetic factors; 17.6% with single genetic risk factor; approximately 50% with two or more risk factors.