Hypercoagulable State and Thrombophilia

Overview

Hypercoagulability/thrombophilia = ↑thrombosis risk from haemostatic imbalance — MIRROR IMAGE of bleeding disorders (balance tips toward clotting instead). Inherited or acquired.

Inherited causes

1. Antithrombin III deficiency — normally binds thrombin, blocks coagulation; deficiency removes this brake
2. Protein C deficiency
3. Protein S deficiency — activated protein C normally inactivates factors V/VIII (cofactor protein S); deficiency of either impairs this
4. Activated protein C resistance (Factor V Leiden) — mutation at the site protein C targets on factor V → factor V resists inactivation even with normal protein C
5. Inherited fibrinolytic pathway disorders (dysfibrinogenaemia, dysplasminogenaemia)
6. ↑Prothrombin production

Acquired causes

1. Antiphospholipid antibodies (APLA) — lupus anticoagulant, anticardiolipin antibodies
2. Impaired venous return (stasis)
3. Oral contraceptives
4. Disseminated malignancy
5. Nephrotic syndrome
6. Postoperative state

Related: pathologic fibrinolysis (opposite extreme)

Fibrinolysis normally protective (limits coagulation). Excessive/unchecked fibrinolysis → BLEEDING (reverse problem). Causes: α2-plasmin inhibitor deficiency (post-trauma/surgery), impaired tPA clearance (liver cirrhosis). Hard to distinguish from secondary fibrinolysis in DIC — both ↑FDP.

Clinical relevance

Hypercoagulable states + bleeding disorders = two ends of SAME haemostatic balance, not separate topics — same components (antithrombin, protein C/S, coag cascade) cause bleeding when deficient one way, thrombosis when their regulatory counterparts fail. Factor V Leiden = gain-of-function-by-RESISTANCE mutation (substrate resists being switched off), distinct mechanism from loss-of-function deficiencies (antithrombin/protein C/protein S) it’s often grouped with. Overlapping acquired risk factors (OCPs, malignancy, postop, nephrotic syndrome) share ONE final common pathway — explains why multiple simultaneous factors compound risk, not just add. Pathologic fibrinolysis = thrombophilia’s bleeding mirror-image — fibrinolytic system dysfunction can push balance either direction (excess→bleeding, deficiency→hypercoagulability).

Overview

Hypercoagulability, or thrombophilia, is a state of increased risk of thrombosis arising from an abnormality in haemostatic equilibrium — conceptually the mirror image of the bleeding disorders covered elsewhere in this section, where the balance instead tips toward abnormal bleeding. It may be inherited or acquired.

Inherited Causes

1. Antithrombin III deficiency — antithrombin III normally binds thrombin, forming a thrombin-antithrombin complex that blocks coagulation; its deficiency removes this natural brake.
2. Protein C deficiency
3. Protein S deficiency — activated protein C normally cleaves and inactivates activated factors V and VIII, an action augmented by cofactor protein S; deficiency of either impairs this anticoagulant mechanism (see Haemostasis Screening Tests).
4. Activated protein C resistance (Factor V Leiden) — a mutation at the site on factor V that activated protein C normally targets, making factor V resistant to inactivation even when protein C itself is normal.
5. Inherited disorders of fibrinolytic pathways — e.g. dysfibrinogenaemia, dysplasminogenaemia.
6. Increased prothrombin production.

Acquired Causes

1. Antiphospholipid antibodies (APLA) — e.g. lupus anticoagulant, anticardiolipin antibodies.
2. Impaired venous return from stasis.
3. Oral contraceptives.
4. Disseminated malignancy.
5. Nephrotic syndrome.
6. Postoperative state.

Related Concept: Pathologic Fibrinolysis (the Opposite Extreme)

Fibrinolysis (plasminogen-plasmin activity, generating FDPs) is normally a protective mechanism limiting coagulation. Unchecked, excessive fibrinolysis can itself cause bleeding rather than thrombosis — the reverse problem from hypercoagulability. Causes include α2-plasmin inhibitor deficiency (post-trauma/surgery) and impaired clearance of tissue plasminogen activator (e.g. in liver cirrhosis). Distinguishing this primary pathologic fibrinolysis from the secondary fibrinolysis that accompanies DIC can be difficult, since both raise FDPs.

Clinical Relevance

• Hypercoagulable states and the classic bleeding disorders are best understood as two ends of the same haemostatic balance, not unrelated topics — the same components (antithrombin, protein C/S, the coagulation cascade) that cause bleeding when deficient or dysfunctional in one direction cause thrombosis when their regulatory counterparts are deficient instead.
• Factor V Leiden is a particularly instructive example of a gain-of-function-by-resistance mutation — the defect is not in an enzyme’s activity but in a substrate’s resistance to being switched off, a distinct mechanistic category from the loss-of-function deficiencies (antithrombin, protein C, protein S) it is often listed alongside.
• Recognising the overlapping acquired risk factors (oral contraceptives, malignancy, postoperative state, nephrotic syndrome) as sharing a final common pathway — tipping the same haemostatic equilibrium toward thrombosis — is more useful clinically than memorising them as an unconnected list, since it explains why patients with multiple simultaneous risk factors (e.g. a postoperative cancer patient on oral contraceptives) face compounding, not merely additive, risk.
• The existence of pathologic fibrinolysis as thrombophilia’s mirror-image bleeding disorder is a useful check on binary thinking about “clotting factors” — the fibrinolytic system is itself a regulated pathway, and its dysfunction in either direction (excess, causing thrombophilia’s opposite; or deficiency, causing hypercoagulability via reduced clot breakdown) can push the haemostatic balance either way.

No Rendered Diagram for This Topic

This topic is a classification of causes (inherited vs acquired) rather than a single shared mechanism — the inherited causes act through several distinct, unrelated pathways (antithrombin, protein C/S, factor V resistance, fibrinolytic defects), so a single process diagram would misrepresent the topic as one pathway when it is genuinely several.

Hand-Draw Suggestion

Draw the normal coagulation-inhibition chain by hand — Antithrombin III ⊣ thrombin, and Protein C (+ cofactor Protein S) ⊣ factors Va/VIIIa — then mark where each inherited defect breaks the chain (deficiency of antithrombin/protein C/protein S removes a brake; Factor V Leiden makes factor V resistant to the brake). This ties the inherited causes back to the coagulation-inhibitor mechanisms already covered in Haemostasis Screening Tests.

Multiple Choice Questions (1)