Critical medicine topic-CMT 016

 PRIMARY HYPERCOAGULABLE STATES

 

 

Definition

Primary hypercoagulable (thrombophilic) states are inherited or acquired disorders characterized by specific laboratory abnormalities that predispose to abnormal blood clot formation.

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Clinical Clues Suggesting a Primary Hypercoagulable State

A thrombophilic disorder should be suspected when thrombosis occurs:

·        At a young age

·        At unusual anatomical sites

·        Recurrently without obvious precipitating factors

·        With a positive family history of thrombosis

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Major Primary Hypercoagulable Disorders

1. Antithrombin III Deficiency

Role of Antithrombin III

·        Major physiological inhibitor of thrombin in the circulation.

·        Prevents excessive clot formation.

Clinical Features

·        Most common primary hypercoagulable disorder (as described in Braunwald).

·        Recurrent deep venous thrombosis (DVT).

·        Recurrent pulmonary embolism (PE).

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2. Protein C Deficiency

Function

Activated Protein C:

·        Inactivates coagulation Factors Va and VIIIa.

·        Promotes fibrinolysis.

Clinical Features

Deficiency results in:

·        Recurrent venous thromboembolism

·        Deep venous thrombosis

·        Pulmonary embolism

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3. Protein S Deficiency

Function

·        Cofactor for activated Protein C.

·        Enhances anticoagulant activity of Protein C.

Clinical Features

Deficiency predisposes to:

·        Recurrent venous thrombosis

·        Venous thromboembolic disease

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4. Lupus Anticoagulant (Antiphospholipid Antibody)

Laboratory Finding

·        Prolonged activated partial thromboplastin time (aPTT).

Clinical Paradox

Despite prolongation of clotting tests, it causes:

·        Increased risk of venous thrombosis

·        Increased risk of thromboembolism

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5. Defective Fibrinolytic System

Venous thrombosis may occur due to:

·        Defective release of tissue plasminogen activator (tPA)

·        Excess tissue plasminogen activator inhibitor (PAI)

Both conditions reduce fibrinolysis and favor clot persistence.

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Secondary Hypercoagulable State

Oral Contraceptive Use

Clinical Association

Associated with:

·        Deep venous thrombosis

·        Pulmonary embolism

·        Coronary thrombosis/embolism

Why It Is Secondary

·        No specific inherited laboratory abnormality.

·        Hypercoagulability is acquired rather than primary.

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Summary Table

Disorder	Defect	Major Clinical Manifestation
Antithrombin III deficiency	Reduced thrombin inhibition	Recurrent DVT, pulmonary embolism
Protein C deficiency	Failure to inactivate Factors Va & VIIIa	Recurrent venous thrombosis
Protein S deficiency	Impaired Protein C function	Recurrent venous thromboembolism
Lupus anticoagulant	Antiphospholipid antibody; prolonged aPTT	Venous thrombosis despite prolonged clotting time
Defective fibrinolysis	↓ tPA release or ↑ PAI	Venous thrombosis
Oral contraceptives	Acquired hypercoagulability	DVT, PE, coronary thrombosis (secondary thrombophilia)

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Key Points

·        Primary thrombophilia is suspected in young patients with recurrent or unexplained thrombosis.

·        Antithrombin III is the major inhibitor of thrombin.

·        Protein C inactivates Factors Va and VIIIa and promotes fibrinolysis.

·        Protein S is the cofactor for activated Protein C.

·        Lupus anticoagulant paradoxically causes thrombosis despite prolonged aPTT.

·        Reduced fibrinolysis due to abnormal tPA/PAI balance predisposes to venous thrombosis.

·        Oral contraceptive use causes an acquired (secondary) hypercoagulable state, not a primary thrombophilia.

 

DR.C.GANESAN M.D.,

PROFESSOR OF MEDICINE