Epidemiology

Factor V Leiden

Common in White population 5%
Point mutation in the F5 gene
- Encodes the factor V protein in the Coagulation Cascade
- This renders factor V (both the activated and inactive forms) insensitive to the actions of activated protein C (аPC)
- Protein C is a natural аոtiϲоаgսlаnt
- This leads to Protein C resistance
- Therefore an increased risk of venous thrοmbοеmbоlism (VTЕ)
Diagnosis
- Genetic testing or a functional test
Management
- Asymptomatic - nil
- Symptomatic - as per normal Deep vein thrombosis.
  - Individualize the duration of аոtiϲοаgսlаtion according to features such as whether the VΤЕ was provoked, life-threatening, or at an unusual site, as done for the general population, rather than a more aggressive approach.

G20210A mutation in the Prothrombin (Factor II) gene
Second most common
Variant is a point mutation in which adenine is substituted for guanine at position 20210 in F2 gene
Mechanism incompletely understood
- Though secondary to increased concentration ad possibility efficiency of prothrombin
Diagnosis
- Genetic test
Treatment similar to Factor V Leiden
- Asymptomatic - nil
- Symptomatic - as per normal Deep vein thrombosis.
  - Individualize the duration of аոtiϲοаgսlаtion according to features such as whether the VΤЕ was provoked, life-threatening, or at an unusual site, as done for the general population, rather than a more aggressive approach.

Decrease in Protein C activity
- Inherited
  - Heterozygous for a genetic defect that reduces protein C levels, activity, or both
- Acquired
  - Disseminated intravascular coagulation (DIC)
  - Liver disease
  - Vitamin K antagonist (VKA) anticoagulants
  - Meningococcal infection
Diagnosis
- Protein C activity levels (low in heterozygotes, ~50% of normal).
- Not accurate during warfarin therapy; consult testing laboratory.
Management
- VTE - if unprovoked typically life long anticoagulation

Hereditary protein S deficiency prevalence is <1% in individuals with VTE.
- Deficiency is autosomal dominant, with most cases due to PROS1 mutation.
Function
- Protein S regulates coagulation negatively.
  - Circulates in free and bound forms (to C4b-binding protein); only the free form is active.
  - Acts as a cofactor for protein C, which inactivates factors Va and VIIIa.
Diagnosis
- Diagnosis is challenging; free protein S levels (measured by immunoassay) are the best screening test.
- Diagnosis requires repeat testing and consideration of family history.
- Misdiagnosis can occur during acute VTE, pregnancy, certain illnesses, or anticoagulant use (especially VKAs).Rare 0.3-2%
Management
- Acute VTE management is similar to the general population: anticoagulation for 3–6 months.
- Indefinite anticoagulation may be indicated for unprovoked VTE, strong family history, or documented deficiency.

Overview
- Antithrombin (AT), also known as AT III or heparin cofactor I, is a natural anticoagulant.
  - Inhibits thrombin (factor IIa), factor Xa, and other serine proteases.
- Hereditary AT deficiency is autosomal dominant with variable penetrance.
  - Rare condition: 0.02–0.2% in the general population.
- Acquired conditions can lower AT levels, but clinical significance is often limited.
- Need antithrombin for platelets to respond to heparin
  - So can present with Heparin resistance
Clinical
- Confers a higher risk of thrombosis compared to other hereditary thrombophilias.
- Presentation varies from no VTE to life-threatening VTE in childhood, early adulthood, or during pregnancy.
- May present as kidney disease or heparin resistance
Diagnosis
- Best initial test: Plasma AT activity (AT-heparin cofactor assay).
- Perform testing post-acute VTE and off anticoagulation therapy.
Management
- Anticoagulation: Standard therapeutic anticoagulation for VTE; prophylaxis in high-risk situations (e.g., pregnancy, surgery).
- AT Concentrate: Replacement therapy using human plasma-derived or recombinant AT in select cases.

Characterised by presence of Antiphospholipid Antibody
- Against plasma proteins bound to anionic phospholipids
  - Lupus Anticoagulant
  - Anticardiolipin
  - Antibodies to B2 Glycoprotein-1
Clinical
- Arterial & venous thrombosis, recurrent fetal loss, thrombocytopenia
- Venous is more common
- Arterial manufactures as stroke
Second hit – smoking, prolonged immobilisation, pregnancy, malignancy
Can be associated with SLE
Management
- Same treatment as other thrombotic disease but lifelong warfarin
- Asymptomatic carriers don’t get started on regular warfarin
- Long-term aspirin if associated with SLE

Heparin-Induced Thrombocytopenia
Liver disease – Antithrombin, Protein C, Protein S
Nephrotic syndrome – Antithrombin
Drugs – Protein C/ protein S, OCP/ HRT
Surgery and trauma
Prolonged immobilization
Older age
Cancer – 15% VTE patients have cancer
Myeloproliferative disorders
Previous thrombosis
Pregnancy and the puerperium
Resistance to activated protein C that is not due to alterations in the factor V gene
Antiphospholipid antibodies – paradoxically prolongs clotting time & increases thrombosis risk
Mild-to-moderate hyperhomocysteinaemia

High
- Recurrent / life threatening DVT
- Family Hx DVT
- < 45 yrs
- No apparent risk factors
- 3 unexplained spontaneous abortions / stillbirths
Moderate
- Unprovoked not in high risk
- Provoked by pregnancy /OCP / HRT
- Unprovoked proximal DVT / PE
- Provoked Proximal DVT & PE
Investigations
Activated Protein C resistance (Factor V Leiden)
- Can also be with OCP, lupus anticoagulant, factor 8, oral anticoagulants, CVA
Factor 8 level
Lupus anticoagulant
Hetero / homozygosity for Factor V Leiden
Hetero / homozygosity for G20210A Prothrombin gene mutation
Homocysteine level
Also with deficiencies of folic acid, B12, B6
Protein C activity
Protein S Ag
AT III
Anticardiolipin antibodies