Overview And Indications For Evaluation

Suspect inherited thrombophilia with recurrent or life-threatening venous thromboembolism (VTE) starting in infancy or childhood.
Indicated by family history of VTE before age 45.
Consider testing lacking acquired risk factors (central venous catheters, immobilization, combined oral contraceptives).
History of multiple spontaneous abortions or stillbirths suggests inherited predisposition.
Multiple gene defects frequently coexist, determining ultimate clinical penetrance and severity.

Pathophysiology And Mechanisms

Impaired neutralization of thrombin causes thrombosis.
Failure to control thrombin generation promotes hypercoagulability.
Malfunction of natural anticoagulant systems disrupts blood fluidity.
Decreased antithrombin (AT) activity impairs thrombin neutralization.
Reduced protein C (PC) or protein S (PS) activity increases thrombin generation.

Single point mutation (G to A) at nucleotide 1691 (or 1765) 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 (3-8% prevalence).
Heterozygotes exhibit 5-10-fold increased VTE risk; homozygotes face 80-fold increased risk.
Oral contraceptive usage synergistically enhances prothrombotic risk.

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 (2-3% Caucasian prevalence).
Homozygotes exhibit less severe clinical presentation compared to homozygous AT, PC, or PS deficiencies.

AT forms complex with activated clotting factors (thrombin, FXa, FIXa, FXIa).
Heparin or cell-surface heparan sulfate dramatically accelerates complex formation.
Type 1 (quantitative defect): Decreased synthesis and functional activity.
Type 2 (qualitative defect): Decreased activity with normal antigenic levels.
Heterozygous state increases VTE risk 10-fold.
Homozygous deficiency likely incompatible with life.

Vitamin K-dependent plasma glycoprotein.
Activated PC inactivates factor Va and factor VIIIa.
Type 1 (quantitative): Decreased plasma concentration and functional activity.
Type 2 (qualitative): Decreased functional activity with normal antigen levels.
Homozygous or compound heterozygous neonates present with purpura fulminans, progressive skin necrosis, and disseminated intravascular coagulation (DIC).
Heterozygous deficiency constitutes major cause of warfarin-induced skin necrosis.

Vitamin K-dependent anticoagulant; functions as cofactor enhancing PC activity against FVa and FVIIIa.
Circulates in free active form (40%) and inactive form bound to C4b-binding protein (60%).
Low free PS levels correlate with thrombotic episodes.
Homozygous or compound heterozygous infants present with purpura fulminans.

Autosomal dominant condition resulting from impaired thrombin binding to abnormal fibrin.
Defective fibrinolysis promotes thrombosis.
Predominantly causes bleeding phenotype, but 20% experience venous or arterial occlusion.
Characterized by prolonged thrombin time, prolonged reptilase time, normal fibrinogen antigen, and reduced fibrinogen activity.

Genetic disorders affecting trans-sulfuration or remethylation pathways of homocysteine metabolism.
Homozygous cystathionine $\beta$-synthetase deficiency causes venous/arterial thrombosis by second decade.
Homozygosity for C677T mutation in methylenetetrahydrofolate reductase (MTHFR) gene causes mild hyperhomocysteinemia.

Lipoprotein(a): Elevated levels compete 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.

Thrombophilia	Inheritance	General Population Prevalence	Laboratory Evaluation
Factor V Leiden	Autosomal Dominant	3-7% (Caucasians)	Gene testing (R506Q mutation); APC resistance assay
Prothrombin 20210	Autosomal Dominant	1-4%	Gene testing (G20210A transition)
Antithrombin Deficiency	Autosomal Dominant	0.02-0.04%	Functional coagulation testing
Protein C Deficiency	Autosomal Dominant	0.2%	Functional coagulation testing
Protein S Deficiency	Autosomal Dominant	0.03-0.13%	Functional testing (Free PS and C4b-binding protein)
Dysfibrinogenemia	Autosomal Dominant	Rare	Thrombin time, reptilase time, fibrinogen activity

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 influence testing: acute thrombosis, infection, inflammation, hepatic dysfunction, nephrotic syndrome, medications, and vitamin K deficiency.
Repeat testing or parental testing recommended to confirm inherited deficiency.

Initiate systemic anticoagulation with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH).
Direct oral anticoagulants (DOACs) or vitamin K antagonists (warfarin) utilized for subsequent outpatient management.

Neonatal Purpura Fulminans (Homozygous PC/PS Deficiency): Empiric replacement with fresh-frozen plasma (FFP) required immediately. Purified PC concentrates available and effective. Long-term oral warfarin indicated.
Warfarin-Induced Skin Necrosis: Requires bridging therapy with heparin when initiating warfarin until target INR attained.
Antithrombin Deficiency: Heparin administration usually ineffective due to deficient AT target. Acute thrombotic episodes managed with AT replacement therapy (FFP, plasma-derived, or recombinant AT concentrates).
Severe Refractory Deficiencies: May require specific factor replacement (PC, PS, or AT concentrates) perioperatively or during acute thrombosis.

Provoked DVT requires $\le$ 3 months anticoagulation; unprovoked requires 6-12 months.
High-risk inherited thrombophilias (PS, PC, AT III deficiency, homozygous FV Leiden, homozygous prothrombin gene mutation) require indefinite lifelong anticoagulation.
Primary prophylaxis (LMWH) indicated for asymptomatic first-degree relatives during high-risk conditions (surgery, trauma, immobilization, postpartum).