Hereditary Prothrombotic States

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.

Specific Inherited Thrombophilias

Factor V Leiden Mutation

• 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.

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

Natural Anticoagulant Deficiencies

Antithrombin Deficiency

• 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.

Protein C Deficiency

• 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.

Protein S Deficiency

• 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.

Dysfibrinogenemia

• 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.

Hyperhomocysteinemia

• 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.

Other Inherited Prothrombotic Risk Factors

• 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.

Clinical Characteristics And Laboratory Profile

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

Diagnostic Nuances In Pediatrics

• 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.

Management Strategies

Acute Thrombosis Management

• 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.

Disease-Specific Interventions

• 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.

Long-Term Prophylaxis

• 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).