hereditary thrombophilia

clinical pearl

Positive results rarely alter acute management. Value lies in prognostication for anticoagulation duration, family counselling, and prophylaxis strategy in high-risk settings (e.g., pregnancy). Thrombosis Canada & Choosing Wisely: Routine testing for Factor V Leiden or Prothrombin Gene Mutation for a first unprovoked VTE adds little value, as recurrence risk is high regardless of genetic status and management is unchanged.

pathophysiology

Genetic defects shifting haemostatic balance toward thrombosis.

• Gain of Function:
  • Factor V Leiden (F5 G1691A): Confers resistance to Activated Protein C (APC).
  • Prothrombin Gene Mutation (G20210A): $\uparrow$ plasma prothrombin levels.
• Loss of Function:
  • Antithrombin Deficiency: $\downarrow$ inhibition of Thrombin, Xa.
  • Protein C Deficiency & Protein S Deficiency: Impaired inactivation of Va/VIIIa.

indications for screening

Screening is selective. Per Thrombosis Canada, do not screen unselected patients with VTE.

Clinical Scenario	Recommendation
Strong Indications	Screen
Unusual Sites	Cerebral sinus, splanchnic/mesenteric veins (Screen Hereditary + Myeloproliferative Neoplasms (JAK2) + Paroxysmal Nocturnal Haemoglobinuria).
Warfarin-induced Skin Necrosis	Suspect Protein C Deficiency.
Heparin Resistance	Suspect Antithrombin Deficiency.
Controversial/Weak Indications	Screening Generally Not Recommended
Unprovoked VTE < 50 yrs	Rarely changes decision to anticoagulate indefinitely.
Strong family history	May inform counselling but often doesn’t change patient’s management.
Arterial Thrombosis (Stroke/MI)	Do not screen. Thrombosis Canada states FVL/PGM are not risk factors for arterial thrombosis. Screen for Antiphospholipid Syndrome in young stroke.
Recurrent Pregnancy Loss (RPL)	Do not screen for hereditary thrombophilias. LMWH shows no benefit for live birth rates (ALIFE2 trial). Screen only for Antiphospholipid Syndrome.

diagnostic timing & interference

Golden Rule: Test 2–4 weeks after discontinuing anticoagulation. Never test during acute thrombosis.

Test	Acute Thrombosis/Inflammation	Heparin	Warfarin	DOACs (Anti-Xa)	Pregnancy
Genetic (FVL / PGM)	Unaffected	Unaffected	Unaffected	Unaffected	Unaffected
Antithrombin (Activity)	$\downarrow$ (Consumption)	$\downarrow$ (False +)	No Effect	Falsely normal/high (masks deficiency)	$\downarrow$
Protein C (Activity)	$\downarrow$ (Consumption)	No Effect	$\downarrow$ (False +)	Falsely normal/high (masks deficiency)	No Effect
Protein S (Free Ag)	$\downarrow$ (False +) (See C4b trap)	No Effect	$\downarrow$ (False +)	Variable	$\downarrow \downarrow$ (Physiologic)
Lupus Anticoagulant	$\uparrow$ CRP interferes	Interferes	Interferes	Interferes (False +)	Difficult

the inflammation trap (protein s)

Free Protein S levels drop during acute inflammation or thrombosis. Inflammation increases C4b-binding protein (an acute phase reactant), which binds free Protein S, causing a falsely low level. Do not diagnose Protein S deficiency if CRP is elevated.

the doac trap (antithrombin & protein c)

Apixaban/Rivaroxaban interfere with chromogenic assays for Antithrombin and Protein C. The drug inhibits the reagent Factor Xa used in the test, causing the assay to report a falsely normal or high activity level. You cannot rule out these deficiencies while a patient is on an anti-Xa DOAC.

specific entities: hereditary

Defect	Mechanism	Relative Risk (VTE)	Key Clinical Notes
Factor V Leiden	APC Resistance	Hetero: 3-5x Homo: 80x	Most common (5% Caucasians). PCR reflex if APC-R assay positive.
Prothrombin Gene Mutation	$\uparrow$ Prothrombin	2-3x	PCR diagnosis only.
Antithrombin Deficiency	Loss of SERPIN	Highest Risk (20-50x)	Can cause heparin resistance. May require AT concentrate.
Protein C Deficiency	$\downarrow$ Va/VIIIa cleavage	10-15x	Risk of Warfarin-induced skin necrosis.
Protein S Deficiency	Cofactor for PC	10-15x	Levels drop physiologically in pregnancy & on oestrogen.

management

• Acute VTE: Standard anticoagulation.
  • Antithrombin Deficiency: If heparin refractory $\to$ Switch to argatroban or use AT concentrate.
• Duration of Anticoagulation:
  • Provoked VTE + Hereditary defect $\to$ Standard 3–6 months.
  • Unprovoked VTE: Decision for indefinite therapy is based on recurrence risk factors (male sex, D-dimer), not solely on thrombophilia status. High-risk defects (AT def, Homo FVL, combined) strengthen the case for indefinite therapy.
• Prophylaxis:
  • Hormones: Avoid oestrogen-containing contraception/HRT in all carriers. Progestin-only options are safer.
  • Pregnancy (Asymptomatic Carriers with no personal VTE hx):
    • Heterozygous FVL/PGM: NO routine prophylaxis.
    • Homozygous FVL or Antithrombin Deficiency: Antepartum & postpartum prophylaxis is strongly considered.
    • Protein C Deficiency/Protein S Deficiency/Homozygous PGM: Decision is individualized based on family history; consult specialist.