Thrombophilia

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.