Hypercoagulable States (Thrombophilia)

1. Primary (inherited/genetic)
2. Secondary (acquired)

1. Primary (Inherited) Hypercoagulable States

A. Factor V Leiden mutation

• Most common inherited thrombophilia.
• Caused by a point mutation in factor V, producing Arg506Gln substitution.
• Mutant factor V becomes resistant to cleavage and inactivation by activated protein C.
• Consequently, the normal protein C anticoagulant pathway is impaired, favoring thrombosis.
• Inherited in an autosomal dominant manner.
• It mainly predisposes to venous thrombosis, especially DVT.
• Heterozygotes have about a 4-8-fold increased relative risk of venous thrombosis; homozygotes have a higher risk.
• Its effect is often apparent only when another risk factor, such as surgery, immobilization, pregnancy, or oral contraceptive use, is also present.

B. Prothrombin gene mutation

• Usually the G20210A mutation in the 3′ untranslated region of the prothrombin gene.
• Leads to increased prothrombin synthesis and hence increased circulating prothrombin levels.
• Increases risk of venous thrombosis.
• Heterozygotes have a roughly 2-4-fold increased risk; the risk is greater in homozygotes.

C. Deficiency of natural anticoagulants

• These disorders commonly present with recurrent venous thrombosis or thromboembolism, often in adolescence or early adulthood.

D. Other inherited causes

• Increased levels of factor VIII, IX, XI, or fibrinogen
• Defects in fibrinolysis
• Homocystinuria due to cystathionine beta-synthase deficiency
• Hyperhomocysteinemia can promote thrombosis through endothelial injury and other prothrombotic effects.

2. Secondary (Acquired) Hypercoagulable States

Important acquired causes

A. Prolonged immobilization

• Bed rest, long-distance travel, paralysis, postoperative state.
• Produces venous stasis and promotes DVT.

B. Tissue injury

• Major surgery, fractures, burns, and trauma.
• Tissue factor release, endothelial injury, inflammation, and immobilization all contribute.

C. Malignancy

• Especially disseminated mucin-producing adenocarcinomas.
• Tumors can release procoagulant substances, including tissue factor-like molecules.
• May produce migratory thrombophlebitis, classically called Trousseau syndrome.

D. Pregnancy, postpartum state, and oral contraceptives

• Hyperestrogenic states increase hepatic synthesis of clotting factors and reduce anticoagulant activity.
• Pregnancy additionally causes venous stasis due to compression of pelvic veins.

E. Antiphospholipid antibody syndrome (APS)

• Antiphospholipid antibodies, including lupus anticoagulant, anticardiolipin antibodies, and anti-beta-2 glycoprotein I antibodies.
• Venous or arterial thrombosis
• Pregnancy morbidity: recurrent miscarriages, fetal death, or premature birth.

• Primary, without another autoimmune disease
• Secondary, most commonly associated with SLE

F. Heparin-induced thrombocytopenia (HIT)

• A serious prothrombotic complication of unfractionated heparin.
• IgG antibodies form against heparin-PF4 complexes.
• Immune complexes activate platelets through Fc receptors.
• This causes:
  • Thrombocytopenia due to platelet removal
  • Marked platelet activation and thrombosis
• Thrombosis can be venous or arterial and can lead to limb gangrene, skin necrosis, stroke, or myocardial infarction.

G. Other acquired conditions

• Myocardial infarction
• Atrial fibrillation
• Prosthetic heart valves
• Cardiomyopathy
• Nephrotic syndrome
• Disseminated intravascular coagulation
• Sickle cell disease
• Smoking
• Obesity
• Advanced age

Key pathogenetic concepts

1. Inherited thrombophilias alone often cause only a moderate rise in risk.
2. Thrombosis commonly follows a multiple-hit model: inherited susceptibility plus an acquired trigger such as immobilization, pregnancy, estrogen therapy, or surgery.
3. Therefore, thrombophilia should be suspected in:
   • Recurrent thrombosis
   • Thrombosis at a young age, particularly before 50 years
   • Thrombosis at unusual sites
   • Strong family history of venous thromboembolism
   • Thrombosis occurring with relatively minor provoking factors

Short exam conclusion